Phytodrug for management of peptic ulcer and methods of preparing and using same

ABSTRACT

A phytochemical composition for management of peptic ulcer conditions in humans is provided. The composition is a hot water extract of powdered  Indigofera arrecta  plant leaves. The extract may be prepared by contacting the powdered leaves with hot water for a period of time, filtering the extraction mixture, concentrating the filtrate in vacuo and freeze drying the concentrated filtrate. The extract is admixed with magnesium carbonate, dried maize starch, talc and magnesium stearate to form a homogenous mass which is filled into capsules. The capsules are ingested orally to provide an analgesic effect. Also described are methods for making the extract and the methodology for using the extract.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/228,107filed on Jan. 11, 1999, now U.S. Pat. No. 6,083,509, which in turn is adivisional of application Ser. No. 08/906,937 filed on Aug. 6, 1997, nowU.S. Pat. No. 6,086,882.

Priority is claimed herein under 35 U.S.C. §119 from application no.RP.12581 filed in Nigeria on Aug. 12, 1996.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of phytodrugs, and inparticular the invention relates to phytodrugs for management of pepticulcer conditions in humans and methods of preparing and using same.

2. Prior Activities and Problems in the Field

Peptic ulcer has been defined as a benign lesion of gastric or duodenalmucosa occurring at a site where the mucosal epithelium is exposed toacid and pepsin. It is a gastrointestinal problem that has beenprevalent in society. The cccurrence of the disease has been associatedwith over-indulgence, inappropriate habit, anxiety and stress.Considerable energy and resources have been expended towards relievingsymptoms of peptic ulcer which usually manifests as an excruciatingpain, especially in the upper abdomen. For centuries neutralization ofgastric acid secretion with antacids and H2-receptor antagonists,provide the only relief from the pains of peptic ulcer. The drugs aregenerally expensive. Consequently, the socio-economic impact of pepticulcer disease on the society can only be imagined.

In the foregoing assertion, efforts have been made to find a suitablepalliative and/or curative agent for the treatment of peptic ulcerconditions from medicinal plants.

It is estimated that approximately 10% of most populations globally willdevelop severe peptic ulcer conditions at some time during theirlifetime. The lesions occur at all ages and affect both sexes.

Authorities estimate that at least five million people suffer fromactive peptic ulcers each year, and approximately 350,000 to 500,000 newcases are diagnosed annually in the United States alone. More than600,000 patients are hospitalized in the U.S. each year for severeepisodes. In approximately one-third of these cases seriouscomplications occur, including intestinal obstruction, uppergastrointestinal hemorrhage and perforation. Furthermore, each year,over 6,000 deaths in the U.S. are directly caused by ulcer disorder. Inaddition, peptic ulcer conditions have been implicated as an indirectcontributing factor in an additional 11,000 deaths each year.

In Nigeria, peptic ulcer conditions general afflict persons between theages of 21 and 51. Duodenal ulcers have their greatest impact in middleage while gastric ulcers become increasingly more frequent withadvancing age.

Peptic ulceration reflects an imbalance between the aggressive action ofacid peptic secretions and the defensive forces that protect the mucosa.Gastric ulcers result from lowered defensive mechanisms and duodenalulcers are the consequence of the destructive action of increasedacid-peptic secretions.

Duodenal ulcers occur when gastric mucosa secretes substantial amountsof acid. Although some patients with duodenal ulcers have normal levelsof acid secretion, on the average they are hyperchlorhydric. Gastricacid has two phases viz;

(1) a cephalic phase (vagally mediated) in which direct cholinergicstimulation of parietal cells induces gastrin release from the antrum,and (2) a less powerful antral phase when food enters the stomach,causing liberation of more gastrin from the antral mucosa.

Evidence that patients with duodenal ulcers have increased parietal cellmass also suggests a genetic predisposition even though experimentaldata indicate that parental cell hyperplasia can be acquired.

Gastric ulceration results from lowering of the gastric mucosalresistance. Principal among the defensive influences is mucoussecretion. The increased frequency of gastric ulcers with advancing agemight be compatible with progressive inability to secrete a protectivelayer of mucous. Chronic gastritis is a frequent concomitant of gastriculcer, is associated with impaired mucous secretion and is alsoage-related. In experimental animals, it has been demonstrated thatprotein depletion, avitaminoses and general malnutrition increase thesusceptibility to gastric ulceration.

There is now growing evidence that Helicobactor pylori, a bacterium maybe the cause of duodenal ulcer. The evidence linking Helicobactor pyloriwith benign gastric ulcer is less convincing than duodenal ulcer.However, the consensus now is that the organism is probably important inthe pathogenesis of 70% of gastric ulcers not attributable to the use ofnon-steroidal anti-inflammatory drugs (NSAIDS).

The symptoms evoked by peptic ulcers are exceedingly variable; someulcers being virtually asymptomatic. Nausea and vomiting may be producedby either duodenal or gastric ulcers, but particularly by the latter.The most consistent manifestation is epigastric pain described variablyas burning, gnawing or boring. Classically, the duodenal ulcer painbecomes most severe two or three hours after the last meal and persistsuntil it is relieved by food or antacids. For this reason, the painrecurs in the middle of the night and requires a glass of milk orantiacid for its relief. Such episodic pain may last for weeks or monthsonly to abate, usually with regulated dietary regimen and therapy.Recurrence is often triggered by dietary indiscretions or stress and isusually very rapid and sometimes dramatic, presenting with hemorrhage orperforation. Death from peptic ulcer is usually due to bleeding orperforation. In addition, a high proportion of patients who die or whoseulcers bleed or perforate have no warning signals.

SUMMARY OF THE INVENTION

In accordance with the present invention, a new drug material extractedfrom Indicofera arrecta (family: papiolionaceae) plant leaves has beenfound to be effective in treating peptic ulcer conditions in humans. Inparticular the invention provides a composition for managing pepticulcer conditions in humans comprising an extract of Indigofera arrectaplant leaves. Generally the composition will comprise a water extract ofIndigofera arrecta plant leaves and in particular the composition maycomprise a hot water extract of powdered Indigofera arrecta plantleaves.

The invention also provides a method for preparing a composition formanaging peptic ulcer conditions in humans. In accordance with theinvention, the method comprises providing a batch of Indigofera arrectaplant leaves; forming a powder from said leaves; and subjecting thepowder to an extraction process to thereby form an extract containing adrug material effective for treating peptic ulcer conditions in humans.Generally speaking, water may be employed as an extraction solvent inthe extraction process, and preferably the extraction process comprisescontacting powdered Indigofera arrecta plant leaves with hot water.

In another aspect of the invention, an admixture is provided fortreating peptic ulcer conditions in humans. The admixture may comprise apowdered extract of Indigofera arrecta plant leaves and an excipientcarrier for said extract. Generally the extract may comprise a hot waterextract of the plant leaves. Preferably, the excipient carrier maycomprise a mixture of heavy magnesium carbonate, dried maize starch,talc and magnesium stearate, and in a particularly preferred form of theinvention, the admixture comprises about 8 to 12 parts by weight of saidleaf extract, about 170 to 180 parts by weight of said heavy magnesiumcarbonate, about 100 to 120 parts by weight of said dried maize starchand about 4 to 6 parts by weight of a talc/magnesium stearate mixture.Ideally the admixture comprises about 2.6 to about 4.3% by weight ofsaid extract.

In yet another form the invention provides a method for treating a humanafflicted with a peptic ulcer condition. In this form of the invention,the method comprises providing a batch Indigofera arrecta plant leaves,subjecting said batch of leaves to a hot water extraction process tothereby form an extract of said Indigofera arrecta plant leaveseffective for treating a peptic ulcer condition, and treating a humanafflicted with a peptic ulcer condition by administering said extractorally to said human. Generally the extraction process may compriseforming a powder from said batch of leaves and contacting said powderwith hot water. Preferably, the extract is mixed with an expicientcarrier material to form an admixture and the treating step comprisesadministering said admixture orally to said human. Ideally, theadmixture of the invention comprises about 2.6 to about 4.3% by weightof said extract.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

In accordance with the invention, a composition for treating andmanaging peptic ulcer conditions in humans is provided. The compositionis prepared by extracting effective peptic ulcer inhibiting chemicalsfrom the powdered leaves of Indigofera arrecta plant. In a preferredform of the invention, the powdered leaves are subjected to a hot waterextraction process whereby the powdered leaves are contacted by hotwater for a period of hours. The extract may be combined with anexcipient carrier material to prepare an admixture which may beencapsulated for oral administration. The admixture, which maypreferably contain from about 2.6 to about 4.3% of the extract byweight, is preferably administered orally to a human patient afflictedby a peptic ulcer condition.

To prepare the extract, the leaves of Indigofera arrectaplant are driedand reduced to a fine powder by grinding with a mortar and pestle orball mill. 500 grams of the finely ground material are then macerated in3 liters of water and heated over a boiling water bath for about 4hours. The resultant mixture is then filtered using filter paper and thefiltrate is concentrated in vacuo to a volume of about 800 ml. Theconcentrate is then freeze-dried for about 48 hours using a Finn AquaLyovac freeze dryer to provide a dry powder containing the active drugmaterials extracted from the initial powdered leaf material. The typicalyield of the extracted material is about 14 to 15% based on the originalweight of the crude ground leaf material. That is to say, the yield isabout 70 to 75 grams when the starting batch is about 500 grams.

Phytochemical screening of the crude ground leaf material revealed thepresence of volatile oils, saponins, tannins and resins. However, onlytannins and saponins were found to be present in the freeze driedextract. Glycosides, anthraquinones, alkaloids, hydrolyzable tannins andresins were all absent from the freeze dried extract. The freeze driedextract contains about 0.02 to 0.04% by weight of volatile oils andabout 7 to 9% by weight of tannins.

The Indigofera arrecta plant was selected as a possible candidate forscientific investigation in the first place and its effectivenessagainst bacteria known to be associated with peptic ulcer conditions wasevaluated using the freeze dried extract. The minimum inhibitoryconcentration and minimum bactericidal concentration of Indigoferaarrecta extract against Ps. Aeruginosa, E. Coli, S. Aureus and B.Subtilis were determined using the agar dilution method. Indigoferaarrecta extract showed potent antimicrobial efficacy against all of thetested commonly encountered microbes. The minimum inhibitoryconcentrations were Ps. Aeruginosa, 0.5 mg/ml; E. Coli, 1 mg/ml; S.Aureus, 1 mg/ml; and B. Subtilis, 1 mg/ml. The minimum bactericidalconcentrations were 1 mg/ml for Ps. Aeruginosa and 2 mg/ml for the otherthree bacteria species. Considering the spectrum of activity ofIndigofera arrecta extract against all the test organisms, it couldpossibly be useful in treating other systemic bacterial infections.

The freeze dried extract of Indigofera arrecta leaves was subjected toacute toxicity test by the intraperitoneal route in mice using standardprocedures. No remarkable adverse effect was observed. The LD₅₀ wasestablished as 245±28 mg/kg i.p.

The target system in peptic ulcer disease is the gastrointestinal tract.Many anti-ulcer agents, especially those that interact with receptorsystems, influence gastrointestinal physiology and its response toulcerogenic substances. Based on this premise, the effect of the freezedried hot water extract of Indigofera arrecta leaves and its interactionwith acetylcholine (Ach) and histamine were investigated on both smoothmuscles and skeletal muscles. The results indicate that the extract ofIndigofera arrecta leaves may contain some anti-spasmodic principleswhich relax the smooth muscles of the gastrointestinal tract.

In a preliminary study, aspirin model of inducing experimental gastriculcer in rats was used to assess the anti-ulcer activity of the extractof Indigofera arrecta leaves which is the subject of the invention. Asshown in Table I, the extract of Indigofera arrecta leaves has aremarkable effect against aspirin-induced ulcers. This effect increasedwith the dose of the extract as shown by the mean ulcer indices.

TABLE I Dose of I. arrecta extract Ulcer Index Normal saline solution1.1 ± 0.07 250 mg of extract/ml of saline 0.5 ± 0.12 500 mg ofextract/ml of saline 0.24 ± 0.02 

Drugs that delay the small intestinal transit time have beneficialeffects on ulcer patients. The effect of the Indigofera arrecta extracton small intestinal transit in mice was tested using the charcoal mealmethod. The results in Table II below show that intraperitonealadministration of the extract in mice significantly reduced smallintestinal transit. The inhibition, however, did not seem to bedose-dependent.

TABLE II Dose of extract % distance traveled % inhibition Normal salinesoln. 92.38 ± 8.8 7.4 250 mg/ml of saline 33.93 ± 1.2 66.07 500 mg/ml ofsaline  61.16 ± 11.3 38.8 Noradrenaline  64.6 ± 9.0 35.4

The Indigofera arrecta extract of the invention showed little tendencyto induce inflammation. In fact, during testing the extract wasadministered i.p. (200 mg/kg) for 1 hour before inflammation wasinduced. On the other hand, the Indigofera arrecta extract at the dosetested did not exhibit potent anti-inflammatory activity. Significant(P<0.05) anti-inflammatory activity was observed, however, 80 min. afteregg-albumin.

The analgesic effect of the Indigofera arrecta extract of the inventionwas tested in thermal pain (Hot plate at 50.2±1° C.) and chemical pain(acetic acid induced writhing). in the two models, it appeared that theIndigofera arrecta extract was ineffective in increasing pain threshold.

Antisecretory activity of the Indigofera arrecta extract of theinvention was also studied. This study was performed in pylorus—ligated(sham) rats. After 48 hours fasting with access to water ad libitum, thepylorus was ligated under pentobarbitone anaesthesia. Pylorus ligationof the rats for 6 hours caused accumulation of gastric secretory volumeand increased gastric acid output. As shown below in Table III, theIndigofera arrecta extract of the invention significantly decreased thevolume and acidity of basal gastric secretions. The number and severityof ulcer were remarkably reduced in animals treated with the Indigoferaarrecta extract of the invention. Moreover, it was determined that theeffect of the extract was dose dependent.

TABLE III Treatment Volume of Acid Output Dosage/Kg gastric secretion(mEq/L) 40 ml saline 3.6 ± 0.19   250 ± 16.4 50 mg I. arrecta extract2.6 ± 0.99 170 ± 6.8 100 mg I. arrecta extract 2.3 ± 0.12 150 ± 8.2

The Indigofera arrecta plant leave extract of the invention wasstandardized and formulated into capsule dosage forms using World HealthOrganization (WHO) guidelines. These guidelines clearly advise that whena plant based product (e.g. herbal medicine) is safe and indicatesefficacy, it can be subsequently standardized and formulated intosuitable dosage for clinical trials. In accordance with acceptedprocedures it has been determined that an appropriate daily dosage ofthe Indigofera arrecta plant leave extract of the present invention isapproximately 2.5 to 5 mg/Kg of body weight administered orally in twodivided doses.

Clinical trials for the Indigofera arrecta leave extract of theinvention commenced using volunteers. The clinical parameter of episodicpain, nausea and vomiting as well as kidney and liver hematologicalstatus and function were assessed. The data obtained so far indicatesthe efficacy of the Indigofera arrecta plant leave extract againstpeptic ulcer with no detectable adverse effects on kidney, liver andblood chemistry. The values recorded for these parameters fall withinnormal ranges. On the average about 80% of those in the test groups haveexperienced relief from episodes of pain since they entered the testprogram.

As a result of the testing to date, it has been determined that anappropriate and effective formulation of the Indigofera arrecta plantleave extract of the invention for oral administration to humans formanaging peptic ulcer conditions includes about 8 to 12 parts by weightof the extract itself, about 170 to 130 parts by weight of heavymagnesium carbonate, about 100 to 120 parts by weight of dried maizestarch and about 4 to 6 parts by weight of a mixture of talc andmagnesium stearate. This formulation is prepared by adsorbing about 200mg of the freeze dried extract, which has a sticky solid mass, in about20 to 25 ml of methanol. The mixture is subjected to evaporation over awater bath leaving a thick liquid mass. About 3 to 4 grams of heavymagnesium carbonate is added as an agent for adsorption, after which themixture is triturated to present a homogenous mass. About 2 to 2.4 gramsof dried maize starch is then added and the mixture again triturated toform a uniform mixture. About 3 to 12 mg of a talc/magnesium stearatemixture is then added and again the mass is mixed until uniformity isattained. The material is then filled into capsules such that eachcapsule contains from about 232 to 306 mq of the uniform mixture. Thedaily dose of the Indigofera arrecta plant leave extract of theinvention then is administered orally as two separate capsules,preferably one in the morning at breakfast time and the other in theevening before bed.

We claim:
 1. An orally administratable human dose form of a therapeuticpeptic ulcer palliating composition comprising an amount of a waterextract of Indigofera arrecta plant leaves effective for peptic ulcerpalliation in a human being and an excipient carrier for said extract.2. A dose form as set forth in claim 1, wherein said comprises a hotwater extract of Indigofera arrecta plant leaves.
 3. A dose form as setforth in claim 1, wherein said excipient carrier comprises magnesiumcarbonate, dried maize starch, talc and magnesium stearate.
 4. A doseform as set forth in claim 3, wherein said composition comprises fromabout 8 to about 12 parts by weight of said leaf extract, from about 170to about 180 parts by weight of said magnesium carbonate, from about 100to about 120 parts by weight of said dried maize starch and from about 4to about 6 parts by weight of a talc/magnesium stearate mixture.
 5. Adose form as set forth in claim 1, wherein said composition comprisesfrom about 2.6 to about 4.3% by weight of said extract.
 6. A dose formas set forth in claim 4, wherein said composition comprises from about2.6 to about 4.3% by weight of said extract.